Condensed 2,3-benzodiazepine derivatives and their use as AMPA-receptor inhibitors

ABSTRACT

Compounds of formula I are described, their production and use in pharmaceutical agents.

[0001] The invention relates to new 2,3-benzodiazepine derivatives,their production and use as pharmaceutical agents.

[0002] It is already known that selected 2,3-benzodiazepine derivativeshave modulatory activity at quisqualate receptors and owing to thisproperty are suitable as pharmaceutical agents for treating diseases ofthe central nervous system.

[0003] It has now been found that the 2,3-benzodiazepine derivativesaccording to the invention are also suitable for treating diseases ofthe central nervous system, whereby the compounds are distinguished bybetter properties compared to the above-mentioned prior art.

[0004] The invention relates to the compounds of formula I

[0005] in which

[0006] R¹ and R² are the same or different and mean hydrogen, C₁-C₆alkyl, nitro, halogen, cyano, the group —NR⁸R⁹, —O—C₁₋₄ alkyl, —CF₃, OHor C₁₋₆ alkanoyloxy,

[0007] R³ and R⁴ are the same or different and mean hydrogen, halogen,C₁-C₆ alkoxy, hydroxy, thiocyanato, C₁-C₆ alkylthio, cyano, COOR¹²,PO₃R¹³R¹⁴, C₁₋₆ alkanoyl, C₁₋₆ alkanoyloxy, C₂₋₆ alkynyl optionallysubstituted with C₁₋₄ alkoxy or phenyl, C₂₋₆ alkenyl optionallysubstituted with C₁₋₄ alkoxy or phenyl; C₁-C₆ alkyl optionallysubstituted by halogen, hydroxy, C₁-C₆ alkoxy, C₁-C₆ thioalkyl,NR¹⁰-R¹¹; C₃₋₇ cycloalkyl, or an optionally substituted aryl or hetarylradical,

[0008] R⁸ and R⁹ are the same or different and mean hydrogen, C₁-C₆alkyl or the group —CO—C₁₋₆ alkyl,

[0009] R¹⁰ and R¹¹ are the same or different and mean hydrogen, C₁-C₆alkyl or C₁₋₆ alkanoyl or together with the nitrogen atom form a 5- to7-membered saturated heterocyle, which can contain another oxygen,sulfur or nitrogen atom and can be substituted,

[0010] R¹², R¹³, R¹⁴ are the same or different and mean H or C₁-C₆alkyl,

[0011] X means hydrogen or halogen,

[0012] Y means C₁₋₆ alkoxy or X and Y together mean —O—(CH₂)_(n)—O—,

[0013] n means 1, 2 or 3, and

[0014] A together with the nitrogen forms a saturated or unsaturatedfive-membered heterocycle, which can contain 1-3 nitrogen atoms and/oran oxgyen atom and/or one or two carbonyl groups or their isomers orphysiologically compatible salts.

[0015] Alkyl is defined in each case as a straight-chain or branchedalkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, pentyl, isopentyl or hexyl.

[0016] R³ and R⁴ in the meaning of C₂₋₆ alkenyl contain at least onedouble bond such as, for example, vinyl, propenyl, buten-1-yl,isobutenyl, penten-1-yl, 2,2-dimethyl-buten-1-yl, 3-methylbuten-1-yl,hexen-1-yl. If R³ or R⁴ means C₂₋₆ alkynyl, at least 1 triple bond ispresent, such as, for example, ethynyl, propynyl, butyn-1-yl,butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl.The alkenyl and alkinyl radicals can be substituted, e.g., with C₁₋₄alkoxy or phenyl, which can be substituted with halogen. If ahalogenated alkyl radical is present, the latter can be halogenated orperhalogenated in one or more places like CF₃.

[0017] Halogen is defined in each case as fluorine, chlorine, bromineand iodine.

[0018] The aryl and hetaryl radicals R³ and R⁴ can be substituted in oneto three places in the same way or differently with halogen, C₁₋₄ alkoxyor C₁₋₄ alkyl.

[0019] The aryl and hetaryl radicals can be present as monocyclic orbicyclic compounds and can contain 5-12 ring atoms, preferably 5-9 ringatoms, such as, for example, phenyl, biphenyl, naphthyl, indenyl as anaryl radical, and thienyl, furyl, pyranyl, pyrrolyl, pyrazolyl, pyridyl,pyrimidinyl, pyridazinyl, oxazolyl, iso-oxazolyl, thiazolyl,isothiazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazolyl-5-yl,1,2,4-oxadiazol-3-yl, quinolyl, isoquinolyl, benzo[1]thienyl,benzofuranyl as a hetaryl radical with 1-3 heteroatoms such as sulfur,oxygen and/or nitrogen. 2-Thienyl, 3-thienyl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl and phenyl can be mentioned as preferred.

[0020] Cycloalkyl is defined in each case as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, especially C₃₋₅ cycloalkyl.

[0021] As alkanoyl radicals, straight-chain or branched aliphaticcarboxylic acid radicals, such as formyl, acetyl, propionyl, butanoyl,isopropylcarbonyl, caproyl, valeroyl, trimethylacetyl, i.a., aresuitable.

[0022] If R¹⁰ and R¹¹ together with the nitrogen atom form aheterocycle, for example, piperidine, pyrrolidine, thiomorpholine,hexahydroazepine, morpholine, piperazine, imidazolidine,hexahydrodiazepine is mentioned. If the heterocycle is substituted, thesubstituent C₁₋₄ alkyl or phenyl can be in one to two places, such as,for example, N-methyl-piperazine, N-phenyl-piperazine,2,6-dimethylmorpholine.

[0023] If A together with the nitrogen atom forms a saturatedheterocycle, the latter can be substituted at the carbon atom or atanother nitrogen atom. In this case, A means, for example, C₃ alkylene,which can be substituted with R³ and R⁴, and in which 1, 2 or 3 alkylenegroups can be replaced by oxygen, carbonyl or —NR³—, such as, forexample, —(CH₂)₃—, —CH₂—NR³—CH₂—, —CH₂—O—CH₂—, —CH₂—O—CO—, —CH₂—NR³—CO—,—CO—NR³—CO— or CH₂—O—CR³R⁴, whereby the carbonyl group is bonded to thenitrogen atom of the benzodiazepine, and R³ and R⁴ preferably mean C₁₋₄alkyl. These compounds of formula I contain a chiral center in the4-position of the 2,3-benzodiazepine skeleton and can be present as aracemate or optical isomers.

[0024] If A together with the nitrogen atom forms an unsaturated5-membered heterocycle, it thus is not a chiral carbon atom, but ratheran exocyclic double bond that is present in the 4-position of the2,3-benzodiazepine skeleton. The unsaturated 5-membered heterocycle canbe present partially unsaturated or aromatic. Preferred areheteroaromatic compounds with 1-3 nitrogen atoms, in which A has, forexample, the following meaning:

[0025] The physiologically compatible salts are derived from inorganicand organic acids. Suitable are inorganic acids, such as, for example,hydrohalic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid, or organic acids such as, for example, aliphatic oraromatic mono- or dicarboxylic acids such as formic acid, acetic acid,maleic acid, fumaric acid, succinic acid, lactic acid, tartaric acid,citric acid, oxalic acid, glyoxylic acid or sulfonic acids, for example,C₁₋₄ alkanesulfonic acids such as methanesulfonic acid orbenzenesulfonic acids that are optionally substituted by halogen or C₁₋₄alkyl, such as p-toluenesulfonic acid.

[0026] The compounds of formula I also comprise all possiblestereoisomers and their mixtures, such as diastereomers, racemates andenantiomers.

[0027] Preferred are compounds of general formula I in which R² meanshydrogen.

[0028] The compounds of general formula I as well as theirphysiologically compatible salts can be used as pharmaceutical agentsowing to their non-competitive inhibition of the AMPA receptors. Owingto their profile of action, the compounds according to the invention aresuitable for treating diseases that are caused by hyperactivity ofexcitatory amino acids, such as, for example, glutamate or aspartate.Since the new compounds act as non-competitive antagonists of excitatoryamino acids, they are suitable especially for treating those diseasesthat are influenced by the receptors of excitatory amino acids,especially the AMPA receptor.

[0029] The pharmacological action of the compounds of formula I wasdetermined by means of the tests described below:

[0030] Male NMRI mice weighing 18-22 g were kept under controlledconditions (0600-1800 hours light/dark cycle, with free access to foodand water) and their assignment to groups was randomized. The groupsconsisted of 5-16 animals. The observation of the animals was performedbetween 0800 and 1300 hours.

[0031] AMPA was sprayed into the left ventricles of mice that wereallowed to move freely. The applicator consisted of a cannula with adevice made of stainless steel, which limits the depth of injection to3.2 mm. The applicator was connected to an injection pump. The injectionneedle was inserted perpendicular to the surface of the skull accordingto the coordinates of Montemurro and Dukelow. The animals were observedup to 180 sec. until clonic or tonic seizures set in. The clonicmovements, which last longer than 5 sec., were counted as seizures. Thebeginning of the clonic seizures was used as an endpoint for determiningthe seizure threshold. The dose that was necessary to raise or reducethe seizure threshold by 50% (THRD₅₀) was determined in 4-5 experiments.The THRD₅₀ and the confidence limit were determined in a regressionanalysis.

[0032] The results of these tests show that the compound of formula Iand its acid addition salts influence functional disorders of the AMPAreceptor. They are therefore suitable for the production ofpharmaceutical agents for symptomatic and preventive treatment ofdiseases that are triggered by changing the function of the AMPAreceptor complex.

[0033] The treatment with the compounds according to the inventionprevents or delays the cell damage that occurs as a result of diseaseand functional disorders and reduces the concomitant symptoms.

[0034] According to the invention, the compounds can be used fortreating neurological and psychiatric disorders that are triggered byoverstimulation of the AMPA receptor. The neurological diseases, whichcan be treated functionally and preventatively, include, for example,neurodegenerative disorders such as Parkinson's disease, Alzheimer'sdisease, Huntington's chorea, amyotrophic lateral sclerosis, andolivopontocerebellar degeneration. According to the invention, thecompounds can be used for the prevention of postischemic cellulardegeneration, cellular degeneration after brain trauma, in the case ofstroke, hypoxia, anoxia and hypoglycemia and for the treatment of seniledementia, AIDS dementia, neurological symptoms that are related to HIVinfections, multiinfarct dementia as well as epilepsy and muscle spasms.The psychiatric diseases include anxiety conditions, schizophrenia,migraines, pain conditions as well as the treatment of sleep disordersand withdrawal symptoms after drug abuse such as in alcohol, cocaine,benzodiazepine or opiate withdrawal. In addition, the compounds can beused in the prevention of tolerance development during long-termtreatment with sedative pharmaceutical agents, such as, for example,benzodiazepines, barbiturates and morphine. Moreover, the compounds canbe used as anesthetics (anesthesia), analgesics or anti-emetics.

[0035] For use of the compounds according to the invention aspharmaceutical agents, the latter are brought into the form of apharmaceutical preparation, which in addition to the active ingredientfor enteral or parenteral administration contains suitablepharmaceutical, organic or inorganic inert media, such as, for example,water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc,vegetable oils, polyalkylene-glycols, etc. The pharmaceuticalpreparations can be present in solid form, for example, as tablets,coated tablets, suppositories, capsules or in liquid form, for exampleas solutions, suspensions or emulsions. Moreover, they optionallycontain adjuvants such as preservatives, stabilizers, wetting agents oremulsifiers, salts for changing the osmotic pressure or buffers.

[0036] For parenteral use, especially injection solutions orsuspensions, especially aqueous solutions of the active compounds inpolyhydroxyethoxylated castor oil, are suitable.

[0037] As vehicle systems, surface-active adjuvants such as salts ofbile acids or animal or vegetable phospholipids, but also mixtures ofthem as well as liposomes or their components, can also be used.

[0038] For oral use, especially tablets, coated tablets or capsules withtalc and/or hydrocarbon vehicles or binders, such as, for example,lactose, corn or potato starch, are suitable. The substance may also beadministered in liquid form, such as, for example, as juice, to whichoptionally a sweetener is added.

[0039] The dosage of the active ingredients can vary depending on methodof administration, age and weight of the patient, type and severity ofthe disease to be treated and similar factors. The daily dose is0.5-1000 mg, preferably 50-200 mg, whereby the dose can be given as asingle dose to be administered once or divided into two or more dailydoses.

[0040] The production of the compounds according to the invention iscarried out for example, in that

[0041] a) a compound of formula II

[0042] in which

[0043] R¹, R², X and Y have the above meaning, is cyclized by reactionof

[0044] α) Z=COOC₁₋₆ alkyl with R³—N═C═O to compounds with A meaning—CO—NR³—CO—

[0045] β) Z=CH₂OH or —CH₂—NHR³ with phosgene to compounds with A meaning—CH₂—O—CO— or —CH₂—NR³—CO—

[0046] γ) Z=—CH₂OH with R³—CO—R⁴ to compounds with A meaning—CH₂—O—CR³R⁴ in which R³ and R⁴ have the above meaning,

[0047] b) a compound of formula III or IV

[0048] in which R¹, R², X and Y have the above meaning, is cyclized byreaction of

[0049] α) Z′=—CH═CH—COOC₁₋₆ alkyl with borane-trimethylamine complex andboron trifluoride etherate to compounds with A meaning —(CH₂)₃— and—(CH₂)₂—CO—

[0050] β) Z′=—CH═N—NH₂ in the presence of copper sulfate to compoundswith A meaning ═CH—N═N—

[0051] γ) Z′=—S—C₁₋₄ alkyl with hydrazine hydrate and acid anhydrides orwith acid hydrazides to compounds with A meaning ═N—N═CR³—

[0052] δ) Z′=—S—C₁₋₄ alkyl with a-aminoacetals to compounds with Ameaning ═N—CR³═CR⁴—

[0053] ξ) Z′=CH₂OH is converted into CH₂NH₂, the latter is acylated andcyclized to compounds with A meaning ═CH—N═CR³—,

[0054] c) a compound of formula V,

[0055] in which R¹, R², X and Y have the meaning given above, is reactedwith α-aminoacetals, α-aminoketals, H₂N—CH₂≡C—R³ or with ammonia andα-haloketones, and then optionally nitro group R¹ and/or R² is reduced,the amino group is acylated or alkylated or converted into halogen orhydroxy or cyano or deaminated or X is dehalogenated simultaneously withthe reduction of the nitro group or in succession or hydrogen issubstituted by halogen or halogen is exchanged for another halogen,—PO₃R¹³R¹⁴, cyano, C₁₋₆ alkanoyl, C₁₋₆ alkanoyloxy, hydroxy, optionallysubstituted C₂₋₆ alkynyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, C₁₋₆ thioalkyl,COOR¹², or Y is re-etherified or the isomers are separated or the saltsare formed.

[0056] It is advisable to carry out the fusing of the heterocycle on2,3-benzodiazepines that are suitably substituted in the 4-position.

[0057] The reaction of the alkyl radical, in which Z=—COO—C₁₋₆ alkyl,with R³—N═C═O in aprotic solvents such as halogenated hydrocarbons atroom temperature or a higher temperature results in compounds of formulaI with A meaning —CO—NR³—CO—. If compounds of formula II in whichZ=—CH₂OH or —CH₂—NHR³ are reacted with phosgene in the presence oftertiary amines in inert solvents, such as optionally halogenatedhydrocarbons, compounds of formula I with A meaning —CH₂—O—CO— or—CH₂—NR³—CO— are obtained.

[0058] If compounds of formula II, in which Z=—CH₂OH, are reacted withcarbonyl compounds in the presence of acids such as hydrochloric acid,compounds of formula I, in which A means —CH₂—O—CR³R⁴—, are obtained ascyclization products.

[0059] If the 2,3-benzodiazepine in the 4-position contains a formylgroup, the latter can be converted in, e.g., a Wittig reaction in theusual way into a compound of formula III, in which Z′=—CH═CH—COO—C₁₋₆alkyl.

[0060] If the acrylic acid ester that is obtained is treated withborane-trimethylamine complex and with boron trifluoride etherate in ahalogenated hydrocarbon such as dichloromethane, compounds of formula Iare obtained with A=—(CH₂)₃— and —(CH₂)₂—CO—, which can be separated bycolumn chromatography. If the 2,3-benzodiazepine that is formylated in4-position is reacted with hydrazine hydrate, the correspondinghydrazone derivative, which is dissolved in polar solvents and mixedwith a solution of copper sulfate in water, is obtained. Compounds offormula I, in which A means ═CH—N═N—, are obtained as cyclizationproducts.

[0061] If a compound of formula III or IV, in which Z′ means C₁₋₄alkyl-S-, is reacted with acid hydrazides in the presence of an acid,e.g., sulfonic acid in an organic solvent, compounds of formula I, inwhich A means ═N—N═CR³—, are obtained. The reaction can also beperformed such that the alkylthio derivative in an organic solvent isheated with hydrazine hydrate, and then is reacted with an acidanhydride to the desired product.

[0062] If the methylthio-benzodiazepine derivative is heated withα-aminoacetals H₂N—CR³H—CH—(O-alkyl)₂, H₂N—CH₂—CR⁴—(O-alkyl)₂ orH₂N—CR³H—CR⁴—(O-alkyl)₂ in the presence of an acid, such asp-toluenesulfonic acid, compounds of formula I with A meaning═N—CR³═CH—, ═N—CH═CR⁴— or ═N—CR³═CR⁴—are obtained.

[0063] The same compounds of formula I can be produced by a compound offormula V being reacted with the corresponding α-aminoacetalNH₂CHR³—CR⁴(OAlk)₂ optionally in solvents such as Cellosolve^((R)) byintroducing an inert gas, such as, e.g., argon or nitrogen to remove thehydrogen sulfide or in the presence of sulfur catchers, such as, e.g.,mercury oxide. Radical (OAlk)₂ is defined as either open orelse—sometimes more advantageously—cyclic acetals or ketals. Compoundsof formula I can also be produced by compounds of formula V beingreacted with propargylamines H₂N—CH₂—C≡CR³ according to processes knownin the literature (Eur. J. Med. Chem. 30, 429 (1995) or Ann. Chem. 1987,(2), 103).

[0064] Compounds of formula I are obtained even if compounds of formulaV with ammonia in solvents such as methanol or Cellosolve^((R))optionally are converted under pressure or with the addition of a sulfurcatcher, such as, for example, silver triflate or mercury oxide, intothe corresponding imine and then reacted with α-haloketones.

[0065] If Z′ is a CH₂OH group, the alcohol can be converted in a knownway by reaction according to Mitsunobu into azide or into phthalimide.Azide can be converted into amine according to methods in literature byreducing agents or by triphenylphosphine. Phthalimide can also beconverted into amine by treatment with hydrazine. The acylation of thisamine is possible with acid chlorides or acid anhydrides according toknown processes. The subsequent cyclization with phosphorus oxychlorideresults in compounds of formula I with A meaning ═CH—N═CR³—.

[0066] The reduction in the nitro group is performed in polar solventsat room temperature or a higher temperature. As catalysts for reduction,metals such as Raney nickel or noble metal catalysts such as palladiumor platinum or else palladium hydroxide optionally on vehicles aresuitable. Instead of hydrogen, for example, ammonium formate,cyclohexene or hydrazine can also be used in a known way. Reducingagents such as tin(II) chloride or titanium(III) chloride can also beused as complex metal hydrides optionally in the presence of heavy metalsalts. Iron can also be used as a reducing agent. The reaction is thenperformed in the presence of an acid such as, e.g., acetic acid orammonium chloride, optionally with the addition of a solvent, such as,for example, water or methanol.

[0067] If alkylation of an amino group is desired, it can be performedaccording to commonly used methods—for example with alkyl halides—oraccording to the Mitsonubo variant by reaction with an alcohol in thepresence of triphenylphosphine and azodicarboxylic acid ester, or theamine can be subjected to reductive amination with aldehydes or ketonesoptionally in succession with two different carbonyl compounds, wherebymixed derivatives are obtained [Bibliography, e.g., Verardo et al.Synthesis (1993), 121; Synthesis (1991), 447; Kawaguchi, Synthesis(1985), 701; Micovic et al. Synthesis (1991), 1043].

[0068] The acylation of an amino group is carried out in the usual way,for example, with an acid halide or acid anhydride optionally in thepresence of a base such as dimethylaminopyridine in solvents such asmethylene chloride, tetrahydrofuran or pyridine, according to theSchotten-Baumann variant in aqueous solution at weakly alkaline pH or byreaction with an anhydride in glacial acetic acid.

[0069] The introduction of the halogens chlorine, bromine or iodine viathe amino group can be carried out, for example, also according toSandmeyer, by the diazonium salts that are intermediately formed withnitrites being reacted with copper(I) chloride or copper(I) bromide inthe presence of the corresponding acid such as hydrochloric acid orhydrobromic acid or with potassium iodide. Instead of diazonium salts,the triazenes optionally also can be used. If an organic nitrite isused, the halogen can be introduced into a solvent such as, for example,dimethylformamide, e.g., by addition of methylene iodide ortetrabromomethane. The removal of the amino group can be achieved eitherby reaction with an organic nitrite in tetrahydrofuran or bydiazotization and reductive boiling-down of diazonium salt with, forexample, phosphorous acid optionally with addition of copper(I) oxide.

[0070] The introduction of fluorine is possible by, for example, BalzSchiemann reaction of diazonium tetrafluoroborate or according to J.Fluor. Chem. 76, 1996, 59-62 by diazotization in the presence of HFxpyridine and subsequent boiling-down optionally in the presence of afluoride ion source, such as, e.g., tetrabutylammonium fluoride.

[0071] The replacement of the amino group by the hydroxy group iscarried out according to methods that are known in the literature,preferably by conversion into triazine and subsequent treatment with astrongly acidic ion exchanger (according to Tetr. Letters 1990, 4409).

[0072] The introduction of halogens into the annelated ring is carriedout according to processes known in the literature, e.g., by reactionwith N-bromo- or N-iodosuccinimide in polar solvents, such astetrahydrofuran, acetonitrile or dimethylformamide or else by reactionwith iodic acid and iodine according to Lieb. Ann. Chem. 634, 84,(1960).

[0073] The exchange of a halogen in the annelated ring is carried out ina way known in the literature optionally under heavy metal catalysis,for example by palladium(II) or palladium(0) compounds by tin-organic orboron-organic compounds, C₂₋₆ alkines, C₂₋₆ alkenes, di- ormon-alkylphosphite, cyanide in solvents such as toluene, tetrahydrofuranor dimethylformamide (M. Kosugi et al. Chem. Lett. 7, 1225, 1984).Optionally, a base, such as, e.g., triethylamine or sodium carbonate,and optionally a co-catalyst, such as, e.g., copper(I) iodide, must beadded.

[0074] Halogens, such as bromine or iodine, can also be reacted withcopper salts, such as copper(I) cyanide (introduction of a nitrilegroup), copper acetate (introduction of an alkanoyloxy group), sodiumalcoholate in the presence of copper(I) iodide (introduction of analkoxy group) or a mixture of copper(I) iodide and sodiumtrifluoroacetate (introduction of a trifluoromethyl group).

[0075] The halogen can also be subjected to a halogen-metal exchange,e.g., by reaction with butyllithium at temperatures of 0° C. to −78° C.in solvents such as ether or tetrahydrofuran optionally with theaddition of complexing agents such as tetramethylethylenediamine, andthen the halogen can be recovered in a way that is known in theliterature with electrophiles, such as, for example, dimethylformamide,alkyl halides such as iodides or chlorides, or aldehydes.

[0076] The isomer mixtures can be separated into enantiomers accordingto commonly used methods, such as, for example, crystallization,chromatography or salt formation.

[0077] The production of salts is carried out in the usual way by asolution of the compound of formula I being mixed with the equivalentamount of acid or excess acid, which optionally is in solution, and theprecipitate being separated or the solution being worked up in the usualway.

[0078] In so far as the production of the starting compounds is notdescribed, the latter are known or can be produced analogously to knowncompounds.

[0079] The invention also comprises the compounds of formulas IIa andIIIa, their isomers and salts

[0080] in which

[0081] R¹, R², X and Y have the above-indicated meaning and

[0082] Z″ means —CH₂OH, —CHO, —COO—C₁₋₆alkyl, CH₂NHR³, COO—C₁₋₆ alkyl

[0083] and R³ has the above-mentioned meaning, which represent valuableintermediate products for the production of pharmacologically activecompounds. The conversion of the intermediate products into activesubstances is carried out according to the processes described above.

[0084] The production of the intermediate products is carried outaccording to known methods or methods that are described here. If the2,3-benzodiazepine in the 4-position contains a methyl group, the lattercan be oxidized to formyl with, for example, SeO₂. Optionally, theformyl group can be reduced to —CH₂OH or oxidized to the carboxyl group,which can then be esterified or the formyl group can be converted into—CH₂NHR³ or subjected to a Wittig reaction.

[0085] The following examples are to explain the process according tothe invention:

Production of the Starting Compounds I.)8-Hydroxymethyl-7-methylcarbamoyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepineA. 8-Formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine

[0086] 1.0 g (3.1 mmol) of8-methyl-5-(4-nitrophenyl-9H-1,3-dioloxol[4,5-h][2,3]benzodiazepine(French Patent No. 2566774) is dissolved at 90° C. in 15 ml of DMF. 0.38g (3.4 mmol) of SeO₂ is added, and it is stirred for 40 minutes at 90°C. After the solid is filtered off, the product is precipitated with 100ml of water, the crude product is filtered off, and it is washed withwater and dried. 1.04 g of the compound is obtained. After purificationby column chromatography (silica gel, eluant benzene/ethyl acetate 20:1)and subsequent suspension of the crystalline compound in ethanol, 0.52 g(50%) of product is obtained. Melting point 228-230° C. (decomposition).

B.8-Hydroxymethyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine

[0087] A suspension of 7.0 g (20.7 mmol) of the aldehyde that isobtained after reaction step A is cooled to 20° C. in 420 ml of ethanolwhile being stirred and mixed little by little with 7.84 g (0.21 mol) ofNaBH₄. The reaction mixture is heated to boiling for 1 hour, then mixedwith activated carbon apd hot-filtered. The solvent is removed, theresidue is taken up in dichloromethane, worked up, and 6.37 g (90%) ofcrude product, which is purified by column chromatography on silica gelwith a 1:1 mixture of benzene/ethyl acetate as an eluant, is obtained.5.46 g (77%) of pure product with melting point 132-134° C. is obtained.

C.8-Hydroxymethyl-7-methylcarbamoyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine

[0088] 1.0 g (2.9 mmol) of the alcohol that is obtained after reactionstep B is dissolved in 40 ml of dichloromethane and mixed with 0.5 ml(8.8 mmol) of methyl isocyanate. The solution is allowed to stand atroom temperature for 3 days and then concentrated by evaporation. Thecrystalline residue is suspended in 10 ml of ethanol and heated toboiling. 1.02 g (87%) of yellow product with a melting point of 242-243°C. (decomposition) is obtained.

II.)5-(4-Aminophenyl)-8-hydroxymethyl-7-methylcarbamoyl-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine

[0089] A suspension of 1.02 g (2.56 mmol) of8-hydroxymethyl-7-methylcarbamoyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine(stage C) in 40 ml of ethanol is mixed with 0.45 ml (9 mmol) of 98%hydrazine hydrate and RaNi catalyst while being stirred. After 30minutes, the catalyst is filtered off, and the solution is concentratedby evaporation. The residue is recrystallized in ethanol, and 0.83 g(88%) of product with a melting point of 136-138° C. is obtained.

III.)8-Hydroxymethyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine

[0090] 2.5 g (7.41 mmol) of8-formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (I,stage A) is suspended in THF:water=1:1 and mixed with 0.14 g (3.7 mmol)of sodium boranate while being stirred and cooled to 20° C. After 45minutes of stirring, it is filtered and the crude product isprecipitated from the filtrate with 130 ml of water. 2.35 g, which isrecrystallized from a mixture of 6.3 ml of dimethylformamide and 1.3 mlof water, is obtained. 1.97 g (78%) of the title compound with a meltingpoint of 175° C. (decomposition) is obtained.

EXAMPLE 19-Methyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[3,4-c][2,3]benzodiazepine-8,10(9H,10aH)-dione

[0091]

A.5-(4-Nitrophenyl)-9H-[1,3-]dioxolo[4,5-h][2,3]-benzodiazepine-8-carboxylicacid

[0092] 42 ml of a 4% NaOH solution is added to a solution of 3.0 g ofAgNO₃ in water (50 ml). The solution of 3.0 g of8-formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h-][2,3]-benzodiazepine in120 ml of dioxane is slowly added to the heterogeneous mixture, and thereaction mixture is stirred for 30 minutes at 25° C. After activatedcarbon is added, it is filtered, the filtrate is concentrated byevaporation in a vacuum at 50-60° C., the suspension that is produced isdiluted with 30 ml of water and cooled. After standing overnight, it isfiltered off, the precipitate is washed with 2×10 ml of ice water, and1.94 g of sodium salt, which is dissolved in 60 ml of hot water and,after cooling, acidified with 1 ml of acetic acid, is obtained. Afterfiltration and washing with water, 1.66 g (53%) of product with amelting point of 196-198° C. (decomposition) is obtained.

B.8-(Methoxycarbonyl)-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine

[0093] 8.0 g (22.0 mmol) of the compound that is obtained after reactionstep A is suspended in 390 ml of methanol and, after 4.2 ml (34.4 mmol)of boron trifluoride etherate is added, the mixture is refluxed for 3hours. The solvent is drawn off, the residue is taken up indichloromethane and 100 ml of a 10% Na₂CO₃ solution, and it is stirredfor 30 minutes. The crude product that is obtained after working-up¹ ispurified by column chromatography (silica gel, eluant: benzene/ethylacetate 20:1), and 3.86 g (46%) of the title compound with a meltingpoint of 235-238° C. (decomposition) is obtained.

C.8-(Methoxycarbonyl)-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine

[0094] A suspension of 2.94 g (8.0 mmol) of the compound that isobtained after reaction step B in 30 ml of dichloromethane is mixed with15 ml of trifluoroacetic acid while being stirred. 6.3 ml (40 mmol) oftriethylsilane is added and stirred for 24 hours at room temperature.Then, it is mixed with 30 ml of dichloromethane, and a solution of 12.3g of Na₂CO₃ in 60 ml of water is added while being stirred and cooledwith ice water. The residue that is obtained after working-up is treatedwith 20 ml of methanol, and 2.85 g (96%) of the title compound with amelting point of 161-164° C. is obtained.

D.9-Methyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[3.4-c][2,3]benzodiazepine-8,10(9H,10aH)-dione

[0095] 0.85 g (2.3 mmol) of the compound that is obtained after reactionstep C is dissolved in 30 ml of dichloromethane, and it is allowed toreact for 3 weeks at room temperature with 1.0 ml (17.5 mmol) of methylisocyanate. The solvent is drawn off, and the residue is purified byboiling with methanol. After suctioning-off, 0.77 g (84%) of the productwith a melting point of 242-244° C. (decomposition) is obtained.

EXAMPLE 25-(4-Aminophenyl)-9-methyl-11H-1,3-dioxolo[4,5-h]imidazo[3,4-c][2,3]benzodiazepine-8,10(9H,10aH)-dione

[0096]

[0097] 0.61 g (1.55 mmol) of the nitro compound that is obtainedaccording to Example 1 is reduced with RaNi/hydrazine hydrate in a 2:1mixture of dichloromethane/methanol. The catalyst is filtered off, thesolution is concentrated by evaporation, the crystalline residue iswashed with water, and 0.54 g (54%) of the title compound with a meltingpoint >270° C. (decomposition) is obtained.

EXAMPLE 39-Methyl-5-(4-nitrophenyl)-9,10,10a,11-tetrahydro-8H-1.3-dioxolo[4,5-i]imidazo[3,4-c][2,3]benzodiazepin-8-one

[0098]

A.8-[(Methylimino)methyl]-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine

[0099] 2.0 g (5.9 mmol) of8-formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine isdissolved in 100 ml of a 1:1 mixture of dichloromethane-methanol, mixedwith 40 ml of a 33% solution of methylamine in ethanol and allowed tostand for 24 hours at room temperature. Then, the solvent is drawn off,and the residue is boiled with 25 ml of ethanol. After filtration, 1.95g (93%) of the title compound with a melting point of 245-247° C.(decomposition) is obtained.

[0100] B.

[0101] 5.5 g (15.7 mmol) of the imine that is obtained after reactionstep A is suspended in 800 ml of ethanol and mixed in portions with 26ml of concentrated HCl while being stirred. 13.6 g (0.36 mmol) of NaBH₄is added to the solution that is obtained for 1 hour in small porions.It is stirred for 30 more minutes, filtered, the filtrate isconcentrated by evaporation and the residue is purified by columnchromatography with methanol as an eluant. 3.67 g (66%) of8-[(methylamino)methyl]-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepinewith a melting point of 110-112° C. is obtained.

C. 9-Methyl-5-(4-nitrophenyl)-9,10,10a,11-tetrahydro-8H-1,3-dioxolo[4,5-h]imidazo[3,4-c][2,3]benzodiazepin-8-one

[0102] 2.26 ml (3.6 mmol) of a 15.6% phosgene solution in toluene isadded drop by drop to a cooled and stirred solution of 1.05 g (3.0 mmol)of the methylaminomethyl compound after reaction step B and 0.99 ml (7.2mmol) of triethylamine in 15 ml of dichloromethane. The mixture isstirred for 2 hours and evaporated to the dry state. The residue istreated with water, and 1.08 g of crude product, which is purified byboiling in 10 ml of ethanol, is obtained. After suctioning-off, 0.96 g(84%) of the title compound with a melting point of 252-255° C. isobtained.

EXAMPLE 4 5-(4-Aminophenyl)-9-methyl-9,10,10a,11-tetrahydro-8H-1,3-dioxolo[4,5-h]imidazo[3,4-c][2,3]benzodiazepin-8-one

[0103]

[0104] 0.38 g (1.0 mmol) of the nitro compound of Example 3 is reducedin 20 ml of methanol with RaNi and hydrazine hydrate analogously toExample 2. After boiling with ethanol, 0.25 g (71%) of the titlecompound of ethanol with a melting point of 280-289° C. (decomposition)is obtained.

EXAMPLE 5 5-(4-Nitrophenyl)-9,10,10a,11-tetrahydro-8H-1,3-dioxolo[4,5-h]pyrrolo[2-c][2,3]benzodiazepine

[0105]

A.Methyl-3-[5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-8-yl]-propenolate

[0106] 1.9 ml (13.6 mmol) of triethylamine and 5.64 g (13.6 mmol) ofmethoxycarbonylmethyl-triphenylphosphonium bromide are added insuccession to a solution of 4.0 g (11.8 mmol) of8-formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine in200 ml of a 1:1 mixture of dichloromethane and methanol while beingstirred. After 2 hours at room temperature, the solvent is drawn offfrom the suspension, the residue is suspended in 70 ml of ethanol andfiltered. After washing three times each with 10 ml of ethanol and 50 mlof water and subsequent drying of the suctioned-off solid, 4.44 g (95%)ofmethyl-3-[5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-8-yl]-propenolatewith a melting point >260° C. is obtained.

B.5-(4-Nitrophenyl)-9,10,10a,11-tetrahydro-8H-1,3-dioxolo[4,5-h]pyrrolo[1,2-c][2,3]benzodiazenine

[0107] 2.22 g (30.4 mmol) of borane-trimethylamine complex is added tothe suspension of 9.0 g (22.9 mmol) of the compound that is obtainedafter stage A in dry dichloromethane (660 ml), and 5.0 ml (40.6 mmol) ofboron trifluoride etherate is added drop by drop while being stirredvigorously. After it was stirred overnight, it is mixed with 300 ml of10% Na₂CO₃ solution, the organic phase is separated and worked up in theusual way. The residue is purified by column chromatography (silica gel,eluant benzene:ethyl acetate=4:0.5). 0.72 g (9%) of the title compoundwith a melting point of 170-172° C. (decomposition) is obtained.

EXAMPLE 65-(4-Nitrophenyl)-9,10,10a,11-tetrahydro-8H-1,3-dioxolo[4,5-h]pyrrolo[2-c][2,3]benzodiazepin[4,5-h]8-one

[0108]

[0109] If the crude product that is obtained according to Example 5 ischromatographed on silica gel with the more polar mixture of ethylacetate:benzene=4:1 as an eluant, 1.26 g (15%) of the title compoundwith a melting point of 251-253° C. (decomposition) is obtained.

EXAMPLE 75-(4-Aminophenyl)-9,10,10a,11-tetrahydro-8H-1,3-dioxolo[4,5-h]pyrrolo[2-c][2,3]benzodiazepine

[0110]

[0111] 0.68 g (1.94) mmol of the nitro compound according to Example 5is reduced in methanol with RaNi/hydrazine hydrate analogously toExample 2. After recrystallization from a mixture of 50% ethanol/water,0.48 g (77%) of the title compound with a melting point of 153-155° C.is obtained.

EXAMPLE 85-(4-Nitrophenyl)-9,10,10a,11-tetrahydro-8H-1,3-dioxolo[4,5-h]pyrrolo[1,2-c][2,3]benzodiazepin[4,5-h]8-one

[0112]

[0113] The compound that is obtained according to Example 6 is reducedin 1:1 dichloromethane/methanol RaNi/hydrazine hydrate analogously toExample 2. After recrystallization from ethanol, 0.8 g (80%) of thetitle compound with a melting point of 291-292° C. (decomposition) isobtained.

EXAMPLE 95-(4-Nitrophenyl)-11H-1,3-dioxolo[4,5-i][1,2,3]triazolo[4,3-c][2,3]benzodiazepine

[0114]

A.8-Formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-hydrazone

[0115] 3.0 g (8.9 mmol) of8-formyl-4-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine issuspended in 18 ml of DMF and mixed with 1.3 ml (26.7 mmol) of 98%hydrazine hydrate and heated for 1 hour to 110-120° C. After cooling toroom temperature, it is added to water, suctioned off, and the residueis washed with water and dried. This crude product is 80% recrystallizedfrom DMF-water. 2.51 g (80%) of the title compound with a melting pointof 221-223° C. (decomposition) is obtained.

B.5-(4-Nitrophenyl)-11H-1,3-dioxolo[4,5-i][1,2,3]triazolo[4,3-c][2,3]benzodiazepine

[0116] 2.0 g (5.7 mmol) of the compound that is obtained after processstep A is dissolved while being heated slightly in 1:1 THF-methanol andmixed with a solution of 7.0 g of CuSO₄•5H₂O in 190 ml of water whilebeing stirred. After 30 minutes, the organic solvent is removed, and theresidue is dissolved in chloroform and water. The organic phase isseparated, washed with water, dried and concentrated by evaporation.After recrystallization from a 10:1 mixture of DMF and water, 1.33 g(67%) of the title compound with a melting point of 257-258° C.(decomposition) is obtained.

EXAMPLE 105-(4-Aminophenyl)-11H-1,3-dioxolo[4,5-i][1,2,3]triazolo[4,3-c][2,3]benzodiazepine

[0117]

[0118] 1.17 g (3.35 mmol) of the nitro compound of Example 9 is reducedin 100 ml of a 1:1 mixture of dichloromethane-methanol withRaNi/hydrazine hydrate analogously to Example 2. After recrystallizationfrom DMF-water (10:1), 0.8 g (74%) of the title compound with a meltingpoint >260° C. (decomposition) is obtained.

EXAMPLE 1110a,11-Dihydro-8,8-dimethyl-5-(4-nitrophenyl)-10H-1,3-dioxolo[4,5-h]oxazolo-[3,4-c][2,3]benzodiazepine

[0119]

[0120] 1.87 g (5.48 mmol) of8-hydroxymethyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepineis dissolved in 25 ml of acetone and mixed with 0.54 ml (6.67 mmol) of37% HCl. After 30 minutes, the reaction mixture is cooled, and thehydrochloride is filtered off. The dichloromethane suspension of thissalt is shaken with 20 ml of 8% NaHCO₃ solution until the salt isdissolved. The organic phase is separated, washed with water, dried andconcentrated by evaporation. After recrystallization, 1.7 g (81%) of thetitle compound, melting point 171-173° C., is obtained.

EXAMPLE 12 5-(4-Aminophenyl)-10a,11-dihydro-8,8-dimethyl-10H-1,3-dioxolo[4,5-h]oxazolo-[3,4-c][2,3]benzodiazepine

[0121]

[0122] Analogously to Example 2, 1.2 g (76%) of the title compound witha melting point of 133-135° C. (ethanol:water=1:1) is obtained from 1.7g (4.46 mmol) of the compound of Example 11 with RaNi/hydrazine hydratein methanol.

EXAMPLE 13 10a,11-Dihydro-5-(4-nitrophenyl)-10H-1,3-dioxolo[4,5-h]oxazolo-[3,4-c][2,3]benzodiazepin-8-one

[0123]

[0124] A s olution of 1.0 g (2.93 mmol) of8-hydroxymethyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]-benzodiazepineis mixed in succession with 0.98 ml (7.03 mmol) of triethylamine and2.23 ml (3.52 mmol) of a 15.6% phosgene solution in toluene while beingstirred and cooled. Then, the reaction mixture is heated for 3 hours to25° C. The precipitate of the crude product is separated, the filtrateis concentrated by evaporation and the residue is treated with water.The combined residues are boiled with ethanol, and after suctioning-off,0.72 g (67%) of the title compound with a melting point >250° C.(decomposition) is obtained.

EXAMPLE 145-(4-Aminophenyl-10a,11-dihydro-10H-1,3-dioxolo[4,5-h]oxazolo-[3,4-c][2,3]benzodiazepin-8-one

[0125]

[0126] 0.5 g (1.36 mmol) of the nitro compound that is obtainedaccording to Example 13 is reduced in DMF with RaNi/hydrazine hydrateanalogously to Example 2. The crude product is purified in 4.5 ml of hotethanol, and 0.49 g (85%) of the title compound with a melting point of173-175° C. is obtained.

EXAMPLE 155-(4-Nitrophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine

[0127]

A. 5-(4-Nitrophenyl)-1,3-dioxolo[4,5-g]-isochroman

[0128] 36.0 g (0.21 mmol) of 2-(1,3-benzodioxol-5-yl)-ethanol is reactedwith an equivalent amount of 4-nitrobenzaldehyde analogously to C.A.105, 1986, 226357, and 50.7 g (81%) of the title compound, melting point149-150° C. (ethanol) , is obtained.

B. 4,5-Methylenedioxy-2-(4-nitrobenzoyl)-phenylacetic acid

[0129] 10.0 g (33.4 mmol) of the isochroman that is obtained afterreaction step A is oxidized to the title compound according to Jones (F.Gatta et al. Il Farmaco 40, 1985, 942-955), yield 46%, melting point237-239° C. (Methyl Cellosolve^((R))) .

C. 5-(4-Nitrophenyl)-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-8(9H)-one

[0130] 5.0 g (15.2 mmol) of the compound that is obtained after reactionstep B is reacted in Methyl Cellosolve^((R)) (50 ml) at 110° C. with 5.0ml of 98% hydrazine hydrate for 2.5 hours. The solvent is drawn off in avacuum, and the residue is dissolved in dichloromethane (200 ml) and 40%acetic acid (20 ml). The organic phase is separated, washed with waterand dried. 4.0 g (19.4 mmol) of 1,3-dicyclohexylcarbodiimide is addedand allowed to stand overnight at room temperature. The precipitate isfiltered off, and the filtrate is concentrated by evaporation. Bothsolids are heated with 60 ml of ethanol and then suctioned off. 1.95 g(39%) of the title compound, melting point 292-294° C., is obtained.

D.5-(4-Nitrophenyl)-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-8(9H)-thione

[0131] 6.5 g (20.0 mmol) of the compound that is obtained after reactionstep C and 7.6 g (30.0 mmol) of phosphorus pentasulfide are heated in100 ml of pyridine to 80° C. After 1.5 hours, the reaction mixture ispoured into 400 ml of water, and the pH of the solution is set at 6.5with acetic acid. The precipitate is filtered off, washed and dried.4.36 g (64%) of product, melting point 257-258° C. (acetone), isobtained.

[0132] Produced analogously via stages A-D are:

[0133]5-(4-Chlorophenyl)-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8(9H)-thione

[0134]5-(4-fluorophenyl)-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8(9H)-thione

[0135]5-(2-fluorophenyl)-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8(9H)-thione

[0136]5-(3-chlorophenyl)-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8(9H)-thione

[0137]5-(2-chlorophenyl)-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8(9H)-thione

[0138] 5-phenyl-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8(9H)-thione

E.8-(Methylthio)-5-(4-nitrophenyl)-9H-1,3-dioxolo-[4,5-h][2,3]benzodiazepine

[0139] 2.2 g (6.45 mmol) of the compound that is obtained after reactionstep D is dissolved in 500 ml of acetone and mixed with 2.22 g of K₂CO₃and 2 ml (32 mmol) of methyl iodide. It is stirred for about 2 days,poured into water, the precipitate is separated, and it is washed withwater. After drying, 2.0 g (87%) of product, melting point 280-281° C.,is obtained.

[0140] Produced analogously are:

[0141]5-(2-Fluorophenyl)-8-(methylthio)-9H-1,3-dioxolo-[4,5-h][2,3]benzodiazepine

[0142]5-(3-chlorophenyl)-8-(methylthio)-9H-1,3-dioxolo-[4,5-h][2,3]benzodiazepine

[0143]5-(2-chlorophenyl)-8-(methylthio)-9H-1,3-dioxolo-[4,5-h][2,3]benzodiazepine

[0144] 8-(methylthio)-5-phenyl-9H-1,3-dioxolo-[4,5-h][2,3]benzodiazepine

F.5-(4-Nitrophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h][2,4]triazolo[4,3-c][2,3]benzodiazepine

[0145] 0.53 g (1.50 mmol) of the compound that is obtained afterreaction step E, 0.22 g (3.0 mmol) of acetic acid hydrazide, and 0.1 gof p-toluenesulfonic acid are heated to 120° C. in 25 ml of MethylCellosolve^((R)) while being stirred. After 45 minutes, the reactionmixture is poured into water, the precipitate is separated, washed withwater and dried. 0.45 g (83%) of product, melting point 292-294° C.(decomposition), is obtained.

EXAMPLE 165-(4-Aminophenyl)-8-methyl-11H-1,3-dioxolo[4.5-h][2,4]triazolo[4,3-c][2,3]benzodiazepine

[0146]

[0147] 0.45 g of the nitro compound that is obtained according toExample 15 is reduced in methanol with RaNi/hydrazine hydrateanalogously to Example 2, and 0.40 g (97%) of product, melting point278-280° C. (ethanol), is obtained.

EXAMPLE 175-(4-Nitrophenyl)-8-ethyl-11H-1,3-dioxolo[4,5-h][2,4]triazolo[4,3-c][2,3]benzodiazenine

[0148]

[0149] Analogously to Example 15, the product is obtained with propionicacid hydrazide after process step F. Yield 71%, melting point 234-235°C.

[0150] Produced in a basically similar way are:

[0151]5-(4-Nitrophenyl)-8-propyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine(melting point 124-126° C.)

[0152]5-(4-nitrophenyl)-8-cyclopropyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine(melting point 154-156° C.)

[0153]5-(4-nitrophenyl)-8-n-butyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine(melting point 124-125° C.)

[0154]5-(4-nitrophenyl)-8-methoxymethyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine(melting point 142-143° C.)

[0155]5-(2-chlorophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine

[0156]5-(3-chlorophenyl)-8-(methyl)-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine

[0157]5-(2-fluorophenyl)-8-(methyl)-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine

[0158]8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine

[0159]8-ethyl-5-phenyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine

[0160]8-cyclopropyl-5-phenyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine

[0161]8-(4-nitrophenyl)-5-phenyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine

EXAMPLE 185-(4-Aminophenyl)-8-ethyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine

[0162]

[0163] The nitro compound that is obtained according to Example 17 isreduced analogously to Example 16. Yield 84%, melting point 265-266° C.(ethanol).

[0164] Produced analogously are:

[0165]5-(4-Aminophenyl)-8-propyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine(melting point 202-203° C., ethyl acetate)

[0166]5-(4-aminophenyl)-8-cyclopropyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine(melting point 191-192° C., ethyl acetate/diethyl ether)

[0167]5-(4-aminophenyl)-8-n-butyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine(melting point 186-187° C., ethyl acetate)

[0168]5-(4-aminophenyl)-8-methoxymethyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine(melting point 261-263° C., ethanol)

[0169]8-(4-aminophenyl)-5-phenyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine

EXAMPLE 195-(4-Nitrophenyl)-8-(4-pyridyl)-11H-1,3-dioxolo[4,5-h][2,4]triazolo[4,3-c][2,3]benzodiazepine

[0170]

[0171] The methylthio derivative that is described in Example 15E isreacted analogously to Example 15F with isonicotinic acid hydrazide inDMF and concentrated hydrochloric acid as a catalyst. Yield 76%, meltingpoint 305-308° C. (decomposition) .

[0172] Produced analogously is:

[0173]5-Phenyl-8-(4-pyridyl)-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine

EXAMPLE 205-(4-Aminophenyl)-8-(4-pyridyl)-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine

[0174]

[0175] The nitro compound of Example 19 is reduced analogously toExample 2. Yield 46%, melting point 301-302° C. (decomposition).

EXAMPLE 215-(4-Nitrophenyl)-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazeiine

[0176]

[0177] 0.53 g of the methylthio compound that is obtained according toExample 15E is reacted analogously to Example 15F with 0.18 g of formicacid hydrazide in DMF with concentrated HCl as a catalyst. Afterchromatography on silica gel with chloroform:methanol=95:5 as an eluant,0.34 g (71%) of product is obtained. Melting point 182-183° C.

[0178] Produced analogously is:

[0179]5-Phenyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine

EXAMPLE 225-(4-Aminophenyl)-11H-1,3-dioxolo[4,5-][2,4]triazolo[4,3-c][2,3]benzodiazepine

[0180]

[0181] The nitro compound that is obtained according to Example 21 isreduced analogously to Example 2. Yield 70%. Melting point 280-281° C.(ethanol).

EXAMPLE 235-(4-Nitrophenyl)-8-(trifluoromethyl)-11H-1,3-dioxolo[4,5-h][2,4]triazolo[4,3-c][2,3]benzodiazepine

[0182]

[0183] 0.53 g (1.50 mmol) of the methylthio compound that is obtained inExample 15E is heated to boiling with 1.5 ml of hydrazine hydrate in 25ml of Methyl Cellosolve^((R)). After 1 hour, the solvent is drawn off,the residue is taken up in water and the precipitate is filtered off.After drying, the compound is dissolved in dichloromethane, and it ismixed drop by drop with 0.40 ml of trifluoroacetic acid anhydride whilebeing stirred and cooled with ice water. The reaction mixture is thenheated to boiling for 1 hour and then evaporated to the dry state. Theresidue is taken up in toluene, heated for 20 minutes, and the solventis then removed. After chromatography on silica gel withchloroform:methanol=95:5 as an eluant, 0.27 g (43%) of product isobtained. Melting point 244-246° C. (methanol).

[0184] Produced analogously is:

[0185]5-Phenyl-8-(trifluoromethyl)-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine

EXAMPLE 245-(4-Aminophenyl)-8-(trifluoromethyl)-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine

[0186]

[0187] The nitro compound that is obtained according to Example 23 isreduced analogously to Example 2. Yield 68%, melting point 206-208° C.(methanol).

EXAMPLE 255-(4-Nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2.3]benzodiazepine

[0188]

[0189] 0.53 g (1.50 mmol) of the methylthio derivative that is obtainedin Example 15E is heated to 120° C. with 0.10 g of p-toluenesulfonicacid and 0.32 g (3.00 mmol).of aminoacetate aldehyde dimethylacetal.After 10 hours, the reaction mixture is poured into water, and theprecipitated intermediate compound is filtered off. This compound isdissolved in 20 ml of a 1:1 mixture of concentrated HCl and ethanol andheated to boiling for 4 hours. After cooling, the hydrochloride of thetitle compound is obtained by filtration. Yield 0.32 g (55%), meltingpoint 237-239° C.

[0190] Produced in a basically similar way is:

[0191] 5-Phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

EXAMPLE 265-(4-Aminophenyl)-11H-13-dioxolo[4,5-h]imidazo[1,2-c][2.3]benzodiazepine

[0192]

[0193] The nitro compound that is produced in Example 25 is reducedanalogously to Example 2. Yield 0.2 g (76%), melting point 264-265° C.(ethanol).

EXAMPLE 276-(4-Aminophenyl)-8-methoxy-3-propyl-11H-[1,2,4]triazolo[4,3-c][2,3]benzodiazelpine

[0194]

[0195] A.

[0196] 3.90 g (10.0 mmol) of7-bromo-8-methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepin-4-oneis dissolved in anhydrous pyridine and mixed with 5.70 g (25.6 mmol) ofphosphorus pentasulfide. After 2 hours at 80° C., the mixture is pouredonto 450 g of ice and stirred for 1 hour. The precipitated crystals arefiltered and washed with water. After recrystallization fromacetonitrile, 2.88 g (71%) of7-bromo-8-methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine-4-thionewith a melting point of 245-247° C. is obtained.

[0197] B.

[0198] 2.84 g (7.0 mmol) of the compound of step A is dissolved in 10 mlof anhydrous DMF and 100 ml of acetone, and after 1.93 g (14.0 mmol) ofpotassium carbonate and 1.75 ml (28.0 mmol) of methyl iodide are added,the mixture is stirred for 20 hours at room temperature. The acetone isthen drawn off, and the residue is taken up in 80 ml of water. Theprecipitated crystals are suctioned off and washed with water. The crudeproduct is recrystallized twice from acetonitrile. 1.68 g (57%) of7-bromo-8-methoxy-4-methylthio-1-(4-nitrophenyl)-5H-2,3-benzodiazepinewith a melting point of 225-227° C. is obtained.

[0199] C.

[0200] 1.17 g (2.78 mmol) of the compound of step B is dissolved in 40ml of anhydrous DMF and mixed with 0.73 g (8.4 mmol) of butyric acidhydrazide as well as 3 drops of concentrated HCl. The mixture is stirredfor 5 hours at 110-115° C. Then, the mixture is poured onto ice (160 g)and stirred for 1 more hour. The precipitated crystals are suctioned offand washed with water. 1.05 g (83%) of9-bromo-6-(4-nitrophenyl)-8-methoxy-3-propyl-11H-[1,2,4]triazolo[4,3-c][2,3]benzodiazepinewith a melting point of 238-240° C. is obtained.

[0201]8-Methoxy-3-methyl-6-(4-nitrophenyl)-11H-[1,2,4]triazolo[4,3-c][2,3]benzodiazepine

[0202]3-ethyl-8-methoxy-6-(4-nitrophenyl)-11H-[1,2,4]triazolo[4,3-c][2,3]benzodiazepine

[0203]3-cyclopropyl-8-methoxy-6-(4-nitrophenyl)-11H-[1,2,4]triazolo[4,3-c][2,3]benzodiazepine

[0204] D.

[0205] 1.0 g (2.2 mmol) of the compound of step C is dissolved in amixture of 80 ml of methanol and 3 ml of water, and after 0.8 g of 10%Pd/C catalyst and 0.30 g (2.2 mmol) of potassium carbonate are added, itis hydrogenated for about 15 hours. Then, catalyst is suctioned out, andthe filtrate is concentrated by evaporation. The crude product isrecrystallized from ethyl acetate (3 ml), and 0.44 g (58%) of6-(4-aminophenyl)-8-methoxy-3-propyl-11H-[1,2,4]triazolo[4,3-c][2,3]benzodiazepinewith a melting point of 192-194° C. is obtained.

[0206] Produced in a basically similar way are:

[0207]6-(4-Aminophenyl)-8-methoxy-3-methyl-11H-[1,2,4]triazolo[4,3-c][2,3]benzodiazepine

[0208]6-(4-aminophenyl)-8-methoxy-3-ethyl-11H-[1,2,4]triazolo[4,3-c][2,3]benzodiazepine

[0209]6-(4-aminophenyl)-8-methoxy-3-cyclopropyl-11H-[1,2,4]triazolo[4,3-c][2,3]benzodiazepine

EXAMPLE 286-(4-Aminophenyl)-8-methoxy-3-methyl-11H-imidazole[1,2-c][2,3]-benzodiazepine

[0210]

[0211] From9-bromo-8-methoxy-3-methyl-6-(4-nitrophenyl)-11H-imidazo[1,2-c][2,3]benzodiazepineanalogously to Example 27D Melting point 190-193° C. (ethyl acetate).

[0212] Produced in a basically similar way are:

[0213]6-(4-Aminophenyl)-8-methoxy-2-methyl-11H-imidazo[1,2-c][2,3]benzodiazepine,melting point 255-260° C. (ethanol), (starting material from Example39).

[0214]6-(4-Aminophenyl)-8-methoxy-3-n-propyl-11H-imidazo[1,2-c][2,3]benzodiazepine,melting point 183-185° C., (starting material from Example 41).

EXAMPLE 299-Methyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4.5-h]imidazo[1,2-c][2,3]benzodiazepine

[0215]

[0216] 1.70 g (4.99 mmol) of5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine-8-thione(Example 15D) and 1.17 g (10.0 mmol) of 2-(1-aminoethyl)-1,3-dioxolane(Shinzo Kano i.a.: Heterocycles 26, 1987, 2805) are stirred with 1.08 gof red mercury oxide in Methyl Cellosolve^((R)) (50 ml) and heated for36 hours to 120° C. The mixture is then filtered and concentrated byevaporation to a volume of 5 ml. The intermediate product thatprecipitates during cooling is suctioned off and dissolved in a 1:1mixture of concentrated hydrochloric acid and ethanol (25 ml) and heatedto boiling for 1.5 hours. After cooling, the hydrochloride of the titlecompound is isolated.

[0217] Yield: 0.70 g (35%), melting point 252-254° C.

EXAMPLE 305-(4-Aminophenyl)-9-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2.3]benzodiazepine

[0218]

[0219] The reduction of the compound of Example 29 is performedaccording to Example 2.

[0220] Yield: 0.37 g (62%), melting point 165-166° C. (ethanol).

EXAMPLE 318-Cyclopropyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0221]

[0222] A suspension of 0.50 g (1.47 mmol) of5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8-thione(Example 15D) and 0.42 g (2.94 mmol) of2-aminomethyl-2-cyclopropyl-1,3-dioxolane in 12 ml of MethylCellosolve^((R)) with 0.32 g (1.47 mmol) of red mercury oxide is stirredfor 12 hours at 110° C. After filtration, the mixture is concentrated byevaporation to a volume of 5 ml and poured into water. The precipitateis suctioned off and dissolved in 10 ml of a 1:1 mixture of concentratedhydrochloric acid and glacial acetic acid and heated to boiling for 1.5hours. During cooling, the hydrochloride salt of the title compoundprecipitates.

[0223] Yield: 0.35 g (56%), melting point 223-225° C.

EXAMPLE 325-(4-Aminophenyl)-8-cyclopropyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2.3]benzodiazepine

[0224]

[0225] The nitro compound that is produced according to Example 31 isreduced analogously to Example 2. The crude product is purified bycolumn chromatography (silica gel, eluant chloroform: methanol=95:5).

[0226] Yield: 0.25 g (85%), melting point 227-229° C. (ethanol).

EXAMPLE 338-Methyl-5-(4-nitrophenyl)1-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0227]

[0228] The reaction is performed analogously to Example 31 from 2.0 g(5.86 mmol) of the thione compound of Example 15D and 1.37 g (11.71mmol) of 2-aminomethyl-2-methyl-1,3-dioxolane (Jiro Adachi and NobuhiroSato: J. Org. Chem. 37, 1972, 221) with 1.27 g (5.86 mmol) of redmercury oxide. The rings of the isolated intermediate compound areclosed by boiling in 50 ml of glacial acetic acid for 5 hours. Then, itis evaporated to the dry state, and the residue is dissolved in 10%sodium carbonate solution and ethyl acetate. After the organic phase isconcentrated by evaporation, the crude product is purified by columnchromatography (silica gel, eluant chloroform:methanol=95:5).

[0229] Yield: 0.80 g (38%), melting point 220-222° C.

EXAMPLE 345-(4-Aminophenyl)8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0230]

[0231] The nitro compound that is produced according to Example 34 isreduced analogously to Example 2.

[0232] Yield: 0.51 g (68%), melting point 283-285° C. (ethanol) .

EXAMPLE 358-Methyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[3,4-c][2,3]benzodiazepine

[0233]

A.5-(4-Nitrophenyl)-8-(phthalimidomethyl)-9H-1,3-dioxolo[4,5-h][2,3-benzodiazepine

[0234] A solution of 1.25 ml (8.05 mmol) of diethyl azodicarboxylate in7 ml of THF is added in drops to a stirred solution of 2.60 g (7.66mmol) of8-hydroxymethyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine(starting compound III.), 2.11 g (8.05 mmol) of triphenylphosphine and1.18 g (8.05 mmol) of phthalimide in 130 ml of dry THF at roomtemperature. The mixture is stirred for 24 hours at this temperature.Then, the precipitated product is suctioned off and washed with ethanol.2.87 g (80%) of the title compound, which can be further processedwithout further purification, is obtained.

B.8-Aminomethyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine

[0235] 0.60 ml (11.7 mmol) of 98% hydrazine hydrate is added to asuspension of 1.10 g (2.35 mmol) of the phthalimido compound fromreaction step A in 75 ml of methanol, and the mixture is heated toboiling for 3 hours. After concentration by evaporation, the residue ispulverized with 30 ml of methylene chloride and filtered off. Thefiltrate is concentrated by evaporation in a vacuum, and the residue isbrought to crystallization with water. After suctioning-off, 0.72 g(90%) of the product with a melting point of 143-146° C., which issuitable for the next step without further purification, is obtained.

C.8-Acetaminomethyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine

[0236] 0.72 g (2.13 mmol) of the aminomethyl compound from step B isdissolved in 6 ml of acetic anhydride at 25° C. and allowed to stand for1 hour. The solution is diluted with ice water (30 ml) and stirred for 2hours. The precipitated substance is filtered and, after drying bycolumn chromatography, purified (silica gel, eluant ethylacetate:benzene=4:1). After the fractions are concentrated byevaporation, 0.65 g of crystalline substance is obtained, which afterwashing with ethanol yields 0.56 g (70%) of pure title compound with amelting point of 205° C. (decomposition).

D.8-Methyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[3,4-c][2,3]benzodiazepine

[0237] 0.40 g (1.05 mmol) of the acetamido compound of step C issuspended in 20 ml of methylene chloride and mixed with 0.48 ml (5.3mmol) of phosphorus oxychloride. Then, the mixture is heated to boilingfor 3 hours. After concentration by evaporation, the residue is taken upin methylene chloride (30 ml) and washed with sodium bicarbonatesolution and water, dried, filtered and concentrated by evaporation.0.38 g of solid substance, which is purified by column chromatography,is obtained (silica gel, eluant chloroform:methanol=95:5). 0.32 g (84%)of pure title compound with a melting point of 305-310° C.(decomposition) is obtained.

[0238] Produced analogously via corresponding stages C-D, whereby themethod used for acylation is placed in parentheses, are

[0239]5-(4-Nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[3,4-c][2,3]benzodiazepine(formic acid, DCC)

[0240] 5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[3,4-c][2,3]benzodiazepine(formic acid, DCC)

[0241]8-cyclopropyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[3,4-c][2,3]benzodiazepine(acid chloride)

[0242]5-(4-nitrophenyl)-8-n-propyl-11H-1,3-dioxolo[4,5-h]imidazo[3,4-c][2,3]benzodiazepine(acid chloride)

EXAMPLE 365-(4-Aminophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[3,4-c][2,3]benzodiazepine

[0243]

[0244] The nitro compound (0.30 g, 0.83 mmol) that is produced accordingto Example 35 is reduced analogously to Example 2. 0.22 g (81%) of thetitle compound with a melting point of 282-284° C. (decomposition) isobtained.

[0245] Produced analogously are:

[0246]5-(4-Aminophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[3,4-c][2,3]benzodiazepine

[0247]8-cyclopropyl-5-(4-aminophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[3,4-c][2,3]benzodiazepine

[0248]5-(4-aminophenyl)-8-n-propyl-11H-1,3-dioxolo[4,5-h]imidazo[3,4-c][2,3]benzodiazepine

EXAMPLE 378-Ethyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[3,4-c][2,3]-benzodiazepine

[0249]

A.8-Azidomethyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine

[0250] A solution of 3.06 g (9.0 mmol) of8-hydroxymethyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine(starting compound III.) and 2.58 g (9.9 mmol) of triphenylphosphine in100 ml of dry tetrahydrofuran is mixed with 13.5 ml of a 1.2N hydrazoicacid solution in toluene, then a solution of 1.74 ml (9.9 mmol) ofazodicarboxylic acid-diethyl ester is added, and the mixture is stirredfor another 2 hours. The precipitated product is suctioned off andwashed with tetrahydrofuran and n-hexane. 2.23 g (68%) of the titlecompound with a melting point of 198-200° C. is obtained.

B.8-Ethyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo][3,4-c][2,3]benzodiazepine

[0251] 1.98 g (5.4 mmol) of the compound from step A is dissolved in 100ml of dry THF and mixed with 1.56 g (5.94 mmol) of triphenylphosphineand stirred for 4 hours. Then, the solution is cooled to −50° C., and asolution of 0.78 ml (6.0 mmol) of propionic acid anhydride in 3 ml ofTHF is added. After 1 hour at −50° C., the mixture is stirred overnightat room temperature. The reaction mixture is then diluted with diethylether and washed with 10% sodium bicarbonate solution and water, driedand concentrated by evaporation. The residue is purified by columnchromatography on silica gel. (Gradient elution: beginning withn-hexane: ethyl acetate=1:1, then with a constantly increasingproportion of ethyl acetate).

[0252] 1.0 g of a product which, after being boiled up in 5 ml of ethylacetate, yields 0.75 g of a mixture of substances, which consists of thetitle compound and the intermediate compound8-propionylaminomethyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine,is obtained.

[0253] To complete the closure of the rings, the above mixture isdissolved in anhydrous dichloroethane and, after 0.20 ml (2.15 mmol) ofphosphorus oxychloride is added, heated to boiling for 2 hours. Thecooled reaction mixture is then washed with sodium bicarbonate solutionand evaporated to the dry state.

[0254] 0.65 g (33%) of the title compound with a melting point of243-245° C. is obtained.

EXAMPLE 38 5-(4-Aminophenyl)-8-ethyl-11H-1,3-dioxolo[4,5-h]imidazo[3,4-c][2,3]benzodiazepine

[0255]

[0256] 0.38 g (1.0 mmol) of the nitro compound that is producedaccording to Example 37 is reduced in 10 ml of a 1:1 mixture ofmethylene chloride and methanol according to Example 2. The crudeproduct is purified by column chromatography (silica gel, eluant:chloroform:methanol=95:5).

[0257] 0.28 g (81%) of the title compound with a melting point of135-138° C. is obtained.

EXAMPLE 399-Ethyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo59[1,2-c][2,3]benzodiazepine

[0258]

[0259] After a catalytic amount of p-toluenesulfonic acid is added, amixture of 1.0 g (2.82 mmol) of8-methylthio-5-(4-nitrophenyl)-9H-1,3dioxolo[4,5-h][2,3]-benzodiazepine(Example 15, step E) and 0.74 g (5.64 mmol) of2-(1-aminopropyl)-1,3-dioxolane (J. Org. Chem. 21, 1956, 115) in 60 mlof Methyl Cellosolve^((R)) is stirred for 48 hours at 120° C. Aftercooling, the unchanged methylthio compound is filtered out, and thefiltrate is concentrated by evaporation to a volume of 10 ml. After 50ml of water is added, the intermediate compound of the condensation stepprecipitates and is suctioned off. The filter residue is dissolved in 10ml of ethanol:concentrated hydrochloric acid=1:1 and heated to boilingfor 1.5 hours. Then, the solution is concentrated by evaporation, andthe residue is taken up in 50 ml of water. It is neutralized with sodiumcarbonate and extracted with ethyl acetate, dried, filtered andconcentrated by evaporation. The residue is purified by columnchromatography (silica gel, eluant: chloroform:methanol=95:5). 0.38 g(36%) of the title compound with a melting point of 188-190° C. isobtained.

[0260] Produced analogously are:

[0261]9-Bromo-8-methoxy-3-methyl-6-(4-nitrophenyl)-11H-imidazo[1,2-c][2,3]benzodiazepine,melting point: 196-200° C.

[0262]9-bromo-8-methoxy-2-methyl-6-(4-nitrophenyl)-11H-imidazo[1,2-c][2,3]benzodiazepine,melting point 265-268° C. (ethanol).

[0263] (Starting material is in each case the compound of Example 27B).

EXAMPLE 405-(4-Aminophenyl)-9-ethyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0264]

[0265] The nitro compound of Example 39 is reduced in methylenechloride:methanol=1:1 analogously to Example 2. After recrystallizationfrom ethyl acetate, 0.14 g (41%) of the title compound with a meltingpoint of 192-194° C. is obtained.

EXAMPLE 415-(4-Nitrophenyl)-8-propyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2.3]benzodiazepinehydrochloride

[0266]

[0267] Produced from 0.68 g (2.0 mmol) of the thione compound (Example15, step D) and 0.58 g (4.0 mmol) of2-aminomethyl-2-propyl-1,3-dioxolane (produced analogously to J. Org.Chem., 37, 1972, 221) and 0.43 g (2.0 mmol) of red mercury oxideaccording to Example 29. After 10 hours at 110° C., the intermediatecompound of the condensation step is purified by chromatography (silicagel, eluant: chloroform-methanol=95:5). Ring-closure reaction isimplemented by heating the intermediate product in a 1:1 mixture ofacetic acid and concentrated hydrochloric acid.

[0268] After the concentration by evaporation, 0.36 g of the titlecompound is obtained as hydrochloride salt.

[0269] Yield 42%, melting point 200-201° C.

[0270] Produced analogously is:

[0271]9-Bromo-8-methoxy-6-(4-nitrophenyl)-3-n-propyl-11H-imidazo[1,2-c][2,3]benzodiazepine,melting point 150-162° C.

EXAMPLE 425-(4-Aminophenyl)-8-propyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0272]

[0273] The nitro compound of Example 41 is reduced analogously toExample 2. After recrystallization from ethanol, 0.27 g (89%) of thetitle compound with a melting point of 175-176° C. (from ethanol) isobtained.

EXAMPLE 438-Ethyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]-benzodiazepinehydrochloride

[0274]

[0275] Produced analogously to Example 41 from 0.68 g (2.0 mmol) of thethione compound (Example 15, step D) and 0.53 g (4.0 mmol) of2-aminomethyl-2-ethyl-1,3-dioxolane (production analogous to J. Org.Chem., 37, 1972, 221). The title compound is isolated as hydrochloride(0.32 g).

[0276] Yield: 39%, melting point 217-218° C.

EXAMPLE 445-(4-Aminophenyl)-8-ethyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0277]

[0278] Produced from the nitro compound of Example 43 according toExample 2. 0.18 g of the title compound is obtained. Yield: 67%, meltingpoint 258-260° C. (ethanol).

EXAMPLE 458,9-Dimethyl-5-(4-nitrophenyl)-11H-[1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepinehydrochloride

[0279]

[0280] The title compound is produced analogously to Example 29 from 2.0g (5.86 mmol) of the thioxo compound of Example 15, step D and 1.54 g(11.72 mmol) of 2-(1-aminoethyl)-2-methyl-1,3-dioxolane (J. Org. Chem.37, 1972, 221) with 1.279 (5.86 mmol) of red mercury oxide. Thecondensation step takes about 30 hours at 110° C. The intermediateproduct is purified by chromatography as in Example 41 and then therings are closed by boiling in 10 ml of a mixture that consists ofethanol-concentrated hydrochloric acid. The title compound is isolatedas hydrochloride: 0.52 g (22%), melting point 240-243° C.

[0281] Produced analogously is:

[0282]9-Bromo-2,3-dimethyl-8-methoxy-6-(4-nitrophenyl)11H-imidazo[1,2-c][2,3]benzodiazepine,melting point: 190-193° C.

EXAMPLE 465-(4-Aminophenyl)-8,9-dimethyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0283]

[0284] The nitro compound of Example 45 is reduced according to Example2. 0.33 g (75%) of the title compound with a melting point of 226-227°C. (ethanol) is obtained.

EXAMPLE 47 A. 4-Nitrobenzoylhydrazone of 2-hydroxy-4-methoxybenzaldehyde

[0285] 63.4 g of 4-nitrobenzhydrazide is introduced into 2.5 1 of1-propanol and mixed with 53.3 g of 2-hydroxy-4-methoxybenzaldehyde andrefluxed for 1 hour. After cooling in an ice bath, it is suctioned off.104 g of the 4-nitrobenzoylhydrazone of 2-hydroxy-4-methoxybenzaldehydeis obtained.

[0286] Produced analogously are:

[0287] Benzoylhydrazone of 2-hydroxy-4-methoxybenzaldehyde

[0288] 4-bromobenzoylhydrazone of 2-hydroxy-4-methoxybenzaldehyde

B. 2-(4-Nitrobenzoyl)-4-methoxybenzaldehyde

[0289] 50 g of 4-nitrobenzoylhydrazone of2-hydroxy-4-methoxybenzaldehyde is introduced into 1.5 1 oftetrahydrofuran (dried on a molecular sieve) at 8° C. and mixed inportions with 99.4 g of lead(IV) acetate (85%). After addition iscompleted, it is stirred for 30 more minutes, suctioned off, and thefiltrate is concentrated by evaporation. The residue is taken up inethyl acetate, washed in succession with water and common salt solution,dried, filtered and concentrated by evaporation. After recrystallizationfrom ethyl acetate, 22.8 g of 2-(4-nitrobenzoyl)-4-methoxybenzaldehydeis obtained.

[0290] Produced analogously are:

[0291] 2-Benzoyl-4-methoxybenzaldehyde

[0292] 2-(4-bromobenzoyl)-4-methoxybenzaldehyde

C. 1-Methoxy-2-(4-methoxy-2-(4-nitrobenzoyl)phenyl)ethylene

[0293] 10 g of 2-(4-nitrobenzoyl)-4-methoxybenzaldehyde is introducedtogether with 18 g of (methoxymethyl)triphenylphosphonium chloride in400 ml of toluene and mixed in portions with 5.9 g ofpotassium-tert-butylate while being cooled with ice. After 1 hour ofstirring while being cooled with ice and a subsequent 3.5 hours ofstirring at room temperature, it is mixed with 200 ml of water, weaklyacidified with 1N hydrochloric acid and extracted three times with ethylacetate. The ethyl acetate phases are washed with saturated common saltsolution, dried, filtered and concentrated by evaporation. The residueis chromatographed on silica gel with hexane:ethyl acetate=1:1 as aneluant. 6.9 g of1-methoxy-2-(4-methoxy-2-(4-nitrobenzoyl)phenyl)ethylene as a mixture ofthe E- and Z-forms is obtained.

[0294] Produced analogously are:

[0295] 1-Methoxy-2-(4-methoxy-2-benzoylphenyl)ethylene.

[0296] 1-Methoxy-2-(4-methoxy-2-(4-bromobenzoyl)phenyl)ethylene.

D. 2-(4-Methoxy-2-(4-nitrobenzoyl)phenyl)acetic acid

[0297] 6.9 g of 1-methoxy-2-(4-methoxy-2-(4-nitrobenzoyl)ethylene as amixture of the E- and Z-forms is introduced into 310 ml oftetrahydrofuran and mixed with 100 ml of 1N hydrochloric acid. Afterstirring overnight at room temperature, it is diluted with 300 ml ofwater, and the tetrahydrofuran is distilled off at a bath temperature of30° C. The aqueous phase is extracted three times with ethyl acetate.The collected organic phase is washed with water, dried, filtered andconcentrated by evaporation. It is taken up in 300 ml of acetone andmixed drop by drop with 11.8 ml of 8N Jones reagent at 40° C. After theaddition is completed, it is stirred for 2 more hours at thistemperature, mixed with 6 ml of isopropanol and stirred for another 15minutes. It is then diluted with 200 ml of water, and the acetone isdrawn off in a rotary evaporator. The aqueous phase is extracted threetimes with ethyl acetate, and the collected organic phase is washed withwater, dried, filtered and concentrated by evaporation. Afterrecrystallization from ethyl acetate/hexane, 6.3 g of2-(4-methoxy-2-(4-nitrobenzoyl)phenyl)acetic acid is obtained.

[0298] Produced analogously are:

[0299] 2-(4-Methoxy-2-benzoylphenyl) acetic acid

[0300] 2-(4-methoxy-2-(4-bromobenzoyl)phenyl) acetic acid

E. 8-Methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazelpin-4-One

[0301] 7.8 g of 2-(4-methoxy-2-(4-nitrobenzoyl)phenyl)acetic acid ismixed in 200 ml of tetrahydrofuran with 2.3 ml of 80% hydrazine hydrateand stirred for 6 hours at room temperature. After standing overnight,it is mixed with 50 ml of water, and the tetrahydrofuran is drawn off ina rotary evaporator. The precipitated2-(4-methoxy-2-(4-nitrobenzoyl)phenyl)acetic acid hydrazide (4.9 g) issuctioned off and stirred in 37 ml of glacial acetic acid at roomtemperature for 2 hours. It is diluted with 37 ml of water and suctionedoff. 4.37 g of8-methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepin-4-one witha melting point of 282° C. is obtained.

[0302] Produced in a basically similar way but with the mixed acidanhydride with isobutyl chloroformate are:

[0303] 8-Methoxy-1-phenyl-4,5-dihydro-3H-2,3-benzodiazepin-4-one

[0304]8-methoxy-1-(4-bromophenyl)-4,5-dihydro-3H-2,3-benzodiazepin-4-one

F.8-Methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine-4-thione

[0305] 4.3 g of8-methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepin-4-one ismixed in 48 ml of pyridine with 2.46 g of diphosphorus pentasulfide andstirred under argon and with exclusion of moisture for 2 hours at a bathtemperature of 100° C. It is diluted with water, and the precipitatedproduct is suctioned off. After chromatography on silica gel first withethyl acetate:hexane=1:1 and later with ethyl acetate, a total of 3.13 gof8-methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine-4-thioneis obtained.

[0306] Produced analogously are:

[0307] 8-Methoxy-1-phenyl-4,5-dihydro-3H-2,3-benzodiazepine-4-thione

[0308]8-methoxy-1-(4-bromophenyl)-4,5-dihydro-3H-2,3-benzodiazepine-4-thione

G. 8-Methoxy-3-methyl-6-phenyl-11H-imidazo[2-c][2,3]benzodiazepine

[0309]

[0310] 500 mng of 8-methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine-4-thione is stirred in 1.5 ml ofethylene glycol monomethyl ether (Cellosolve^((R))) and 548 mg of2-aminomethyl-2-methyl-1,3-dioxolane while argon is passing through itfor 10 hours at 60° C. After filtration and washing with cold ethanoland disopropyl ether, 550 mg of imino compound, which is dissolved in 10ml of ethanol, mixed with 10 ml of concentrated hydrochloric acid andrefluxed for 3 hours, is obtained. It is added to water, set at pH 11and extracted with ethyl acetate. The ethyl acetate phase is washed withwater, dried, filtered and concentrated by evaporation. Afterrecrystallization from ethyl acetate/diisopropyl ether, 240 mg of8-methoxy-3-methyl-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine with amelting point of 140° C. is obtained.

[0311] Produced analogously from the corresponding thiones are:

[0312] 8-Methoxy-2-methyl-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine

[0313] 8-methoxy-3-methyl-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine

[0314]8-methoxy-3-ethyl-2-methyl-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine

[0315]8-methoxy-6-phenyl-3-(4-pyridyl)-11H-imidazo[1,2-c][2,3]benzodiazepine²

[0316]8-methoxy-6-phenyl-3-(2-pyridyl)-11H-imidazo[1,2-c][2,3]benzodiazepine²

[0317]8-methoxy-6-phenyl-3-(3-pyridyl)-11H-imidazo[1,2-c][2,3]benzodiazepine²

[0318]3,6-diphenyl-8-methoxy-2-methyl-11H-imidazo[1,2-c][2,3]benzodiazepine

[0319]8-methoxy-6-(4-nitrophenyl)-3-(2-pyridyl)-11H-imidazo[1,2-c][2,3]benzodiazepine

[0320]8-methoxy-6-(4-nitrophenyl)-3-(4-pyridyl)-11H-imidazo[1,2-c][2,3]benzodiazepine

[0321]5-(4-chlorophenyl)-8,9-dimethyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0322]9-ethyl-8-methyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0323]8-ethyl-9-methyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0324]5-(4-nitrophenyl)-8-(4-pyridyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine²

[0325]8,9-dimethyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

EXAMPLE 482.3-Dimethyl-6-(4-nitrophenyl)-8-methoxy-11H-imidazo[1,2-c][2.3]benzodiazepine

[0326]

[0327] 2.3 g of8-methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine-4-thioneis stirred with 3 ml of 2-amino-3,3-dimethoxybutane (produced byreductive amination according to J. Org. Chem. 52, (12), 2616 from3,3-dimethoxybutan-2-one) while argon is passing through it for 4 hoursat a bath temperature of 110° C. The preparation is mixed with 50 ml of1N hydrochloric acid, diluted with water to 100 ml and extracted threetimes with 150 ml of ethyl acetate each. The aqueous phase is madealkaline with a 1N sodium hydroxide solution and extracted three timeswith ethyl acetate. The collected organic phases are dried, filtered andconcentrated by evaporation, and the residue is chromatographed onsilica gel with methylene chloride:ethanol=10:1 as an eluant. 1.5 g of2,3-dimethyl-8-methoxy-6-(4-nitrophenyl)-11H-imidazo[1,2-c]benzodiazepineis obtained.

[0328] Produced analogously are:

[0329]6-(4-Bromophenyl)-2,3-dimethyl-8-methoxy-11H-imidazo[1,2-c][2,3]benzodiazepine

[0330]2,3-dimethyl-8-methoxy-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine

[0331]8,9-dimethyl-5-(4-fluorophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

EXAMPLE 49 A.6-(4-Aminophenyl)-2,3-dimethyl-8-methoxy-11H-imidazo[1,2-c][2,3]benzodiazepine

[0332]

[0333] 834 mg of2,3-dimethyl-8-methoxy-6-(4-nitrophenyl)-11H-imidazo[1,2-c][2,3]benzodiazepinein 33 ml of glacial acetic acid together with 2.25 g of iron powder areheated for 20 minutes in an oil bath that is preheated to 90° C. It issuctioned off hot and rewashed with glacial acetic acid. The filtrate isconcentrated by evaporation, and the residue is dispersed in ethylacetate and 1N sodium hydroxide solution. The aqueous phase is shakenout twice with ethyl acetate, and the collected organic phase is washedwith water, dried, filtered and concentrated by evaporation. Thisresidue is chromatographed on silica gel with methylenechloride:ethanol=10:1 as an eluant. After the corresponding fractionsthat are concentrated by evaporation are absorptively precipitated withethyl acetate/hexane, 331 mg of6-(4-aminophenyl)-2,3-dimethyl-8-methoxy-11H-imidazo[1,2-c][2,3]benzodiazepinewith a melting point of 280° C. is obtained.

[0334] Produced analogously are:

[0335]6-(4-Aminophenyl)-8-methoxy-3-(2-pyridyl)-11H-imidazo[1,2-c][2,3]benzodiazepine

[0336]6-(4-aminophenyl)-8-methoxy-3-(4-pyridyl)-11H-imidazo[1,2-c][2,3]benzodiazepine

[0337]5-(4-aminophenyl)-9-bromo-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo][1,2-c][2,3]benzodiazepine

[0338]5-(4-aminophenyl)-8-bromo-9-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

B.5-(4-Aminophenyl)-8-ethyl-9-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2c-][2,3]benzodiazepine

[0339]

[0340] 527 mg of8-ethyl-9-methyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepineis mixed in 11 ml of ethanol with 5.4 ml of cyclohexene and 106 mg ofpalladium hydroxide on carbon (Pearlman's catalyst), and it is stirredfor 3 hours at a bath temperature of 110° C. After catalyst is filteredout, it is concentrated by evaporation, and the residue ischromatographed on silica gel with ethyl acetate as an eluant. Aftercombining the corresponding fractions and recrystallization fromethanol, 348 mg of5-(4-aminophenyl)-8-ethyl-9-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepinewith a melting point of 227-228° C. is obtained.

[0341] Produced analogously are:

[0342]5-(4-Aminophenyl)-8-(4-pyridyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0343]5-(4-aminophenyl)-9-ethyl-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

EXAMPLE 508-Methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0344]

[0345] 200 mg of5-(4-aminophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepineis mixed in 30 ml of tetrahydrofuran with 1.32 ml of pentyl nitrite andrefluxed under argon for 2 hours. After concentration by evaporation, itis chromatographed on silica gel with methylene chloride:ethanol=10:1.136 mg of8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepineis obtained.

EXAMPLE 515-(4-Chlorophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0346]

[0347] 160 mg of5-(4-aminophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepineis dissolved in 2 ml of water and 2 ml of concentrated hydrochloricacid, and it is diazotized at 0° C. with a solution of 36 mg of sodiumnitrite in 0.5 ml of water. Stirring is continued for 45 minutes at 0°C. To this solution at room temperature is added in drops a solutionwhich is prepared as follows: 256 mg of copper sulfate pentahydrate ismixed in 1 ml of water with 87 mg of sodium chloride and mixed drop bydrop with a solution of 68 mg of sodium sulfite in 0.6 ml of water. Thewhite precipitate is separated from the supernatant by decanting, washedtwice with water and dissolved in concentrated hydrochloric acid. Afterthis solution is added, it is heated for 10 minutes in a steam bath andstirred for 1 more hour at room temperature. It is diluted with water,made alkaline with ammonia solution and extracted with ethyl acetate.The ethyl acetate phase is washed with saturated sodium chloridesolution, dried, filtered and concentrated by evaporation. Afterchromatography on silica gel with methylene chloride:ethanol=10:1, 87 mgof5-(4-chlorophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepineis obtained.

EXAMPLE 525-(4-Fluorophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0348]

[0349] First 200 mg of5-(4-aminophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepineis added to a solution of 6 ml of hydrogen fluoride-pyridine complex(1:1) under argon, and then 51 mg of sodium nitrite is added at 0-5° C.After stirring at 5-10° C. for 40 minutes, 117 mg of tin(II) chlorideand 190 mg of tetrabutylammonium dihydrogen trifluoride are added to thepreparation. It is then heated for 3 hours to a bath temperature of 100°C. After cooling, it is added to ice water and extracted three timeswith ethyl acetate and three times with methylene chloride. Thecollected organic phase is dried, filtered, concentrated by evaporationand chromatographed on silica gel first with methylenechloride:ethanol=10:1, then a second time with acetone:ethyl acetate=3:1and then a third time with methylene chloride:ethanol=95:5. 106 mg of5-(4-fluorophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepinewith a melting point of 190° C. is obtained.

EXAMPLE 539-Bromo-8-methyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4.5-h]imidazo[1,2-c][2,3]benzodiazepine

[0350]

[0351] 900 mg of8-methyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepineis mixed in 10 ml of dimethylformamide with 441 mg of N-bromosuccinimideand stirred for 1.5 hours at room temperature. After dilution with 40 mlof water, the precipitated product is suctioned off, and 900 mg of9-bromo-8-methyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepineis obtained.

[0352] Produced analogously are:

[0353]8-Bromo-9-methyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0354]2-bromo-8-methoxy-3-methyl-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine

[0355]2-bromo-8-methoxy-6-phenyl-3-(3-pyridyl)-11H-imidazo[1,2-c][2,3]benzodiazepine

[0356]8,9-dibromo-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine(with excess N-bromosuccinimide)

[0357]3-bromo-8-methoxy-2-methyl-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine

[0358]8-iodo-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepinewith N-iodosuccinimide

EXAMPLE 542-Acetyl-3-(3-pyridyl)-8-methoxy-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine

[0359]

[0360] 82 mng of2-bromo-3-(3-pyridyl)-8-methoxy-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepineis mixed in 3 ml of toluene and 0.5 ml of dimethylformamide with 650 mgof (1-ethoxyvinyl)tributylstannane and 10 mg ofpalladium(O)tetrakistriphenylphosphine, and it is heated for 4 hours toa bath temperature of 120° C. Then, (1-ethoxyvinyl)tributylstannane and10 mg of palladium(O)tetrakistriphenylphosphine are added again, and itis heated for 10 hours to a bath temperature of 120° C. After cooling,it is mixed with 2 ml of 1N hydrochloric acid, stirred for 10 minutes,made alkaline with ammonia and shaken out with ethyl acetate. The ethylacetate phase is washed with water and saturated common salt solution,dried, filtered and concentrated by evaporation. After chromatography ofthe residue on silica gel with ethyl acetate as an eluant, 20 mg of2-acetyl-3-(3-pyridyl)-8-methoxy-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepineis obtained.

[0361] Obtained analogously are:2-Vinyl-3-(3-pyridyl)-8-methoxy-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine,

[0362]9-propinyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepinewith the addition of a Cu(I) co-catalyst.

EXAMPLE 55

[0363]

[0364]120 mg of9-bromo-8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepineis mixed in 15 ml of tetrahydrofuran at −78° C. with 0.36 ml ofbutyllithium (hexane, 1 mol) and stirred for 15 minutes. It is thenmixed at this temperature with 0.6 ml of dimethylformamide and stirredfor 15 minutes. After stirring to room temperature, it is mixed withwater, the tetrahydrofuran is distilled off and extracted with ethylacetate. After the solvent is distilled off, it is chromatographed onsilica gel with dichloromethane:ethanol=95:5 as an eluant. 46 mg of9-formyl-8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepineis obtained.

[0365] Produced in a basically similar way are:

[0366]9-(1-Hydroxyprop-1-yl)-8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0367]9-ethyl-8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0368]9-methoxymethyl-8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

EXAMPLE 56

[0369]100 mg of9-iodo-8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]-imidazo[1,2-c][2,3]benzodiazepineis provided, dissolved in 4 ml of toluene and 1.5 ml of ethanol. 54 mgof diethyl-3-pyridyl-borane, 20 mg oftetrakis(triphenylphosphine)-palladium (0) and 0.8 ml of a 2 M Na₂CO₃solution are added, and it is stirred for 3 hours at 110° C. After wateris added, it is extracted using ethyl acetate, and the organic phase isconcentrated by evaporation. This residue is chromatographed on silicagel with dichloromethane:ethanol=95:5 as an eluant. 13 mg of8-methyl-5-phenyl-9-(3-pyridyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c]benzodiazepineis obtained.

[0370] Produced analogously from9-iodo-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepineis:

[0371]9-(3-Pyridyl)-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

EXAMPLE 57

[0372]100 mg of9-iodo-8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepineis stirred in 2 ml of dimethylformamide, 0.03 ml of triethylamine, 0.032ml (30 mg) of diethyl phosphite and 15 mg oftetrakis(triphenylphosphine)-palladium(O) at 1000° C. for 2 hours. Then,it is diluted with 10 ml of water and extracted with ethyl acetate. Theorganic phase that is concentrated by evaporation is chromatographed onsilica gel with dichloromethane:ethanol=95:5 as an eluant. 10 mg of8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine-9-phosphonicacid diethyl ester is obtained.

1. Compounds of formula I

in which R¹ and R² are the same or different and mean hydrogen, C₁-C₆alkyl, nitro, halogen, cyano, the group —NR⁸R⁹, —O—C₁₋₄ alkyl, —CF₃, OHor C₁₋₆ alkanoyloxy, R³ and R⁴ are the same or different and meanhydrogen, halogen, C₁-C₆ alkoxy, hydroxy, thiocyanato, C₁-C₆ alkylthio,cyano, COOR¹², PO₃R¹³R¹⁴, C₁₋₆ alkanoyl, C₁₋₆ alkanoyloxy, C₂₋₆ alkynyloptionally substituted with C₁₋₄ alkoxy or phenyl, C₂₋₆ alkenyloptionally substituted with C₁₋₄ alkoxy or phenyl; C₁-C₆ alkyloptionally substituted by halogen, hydroxy, C₁-C₆ alkoxy, C₁-C₆thioalkyl, NR¹⁰-R¹¹; C₃₋₇ cycloalkyl, or an optionally substituted arylor hetaryl radical, R⁸ and R⁹ are the same or different and meanhydrogen, C₁-C₆ alkyl or the group —CO—C₁₋₆ alkyl, R¹⁰ and R¹¹ are thesame or different and mean hydrogen, C₁-C₆ alkyl or C₁₋₆ alkanoyl ortogether with the nitrogen atom form a 5- to 7-membered saturatedheterocyle, which can contain another oxygen, sulfur or nitrogen atomand can be substituted, R¹², R¹³, R¹⁴ are the same or different and meanH or C₁-C₆ alkyl, X means hydrogen or halogen, Y means C₁₋₆ alkoxy or Xand Y together mean —O—(CH₂)_(n)—O—, n means 1, 2 or 3, and A togetherwith the nitrogen forms a saturated or unsaturated five-memberedheterocycle, which can contain 1-3 nitrogen atoms and/or an oxygen atomand/or one or two carbonyl groups or their isomers or physiologicallycompatible salts. 2.5-(4-Aminophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine5-(4-aminophenyl)-8-cyclopropyl-11H-1,3-dioxolo[4,5-h][1,2,4]triazolo[4,3-c][2,3]benzodiazepine6-(4-aminophenyl)-8-methoxy-3-propyl-11H-[1,2,4]triazolo[4,3-c][2,3]benzodiazepine6-(4-aminophenyl)-8-methoxy-3-ethyl-11H-[1,2,4]triazolo[4,3-c][2,3]benzodiazepine6-(4-aminophenyl)-8-methoxy-3-cyclopropyl-11H-[1,2,4]triazolo[4,3-c][2,3]benzodiazepine5-(4-aminophenyl)-9-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine5-(4-aminophenyl)-8-cyclopropyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine5-(4-aminophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine8-cyclopropyl-5-(4-aminophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[3,4-c][2,3]benzodiazepine5-(4-aminophenyl)-9-ethyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine5-(4-aminophenyl)-8,9-dimethyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine8-methoxy-3-methyl-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine8-methoxy-2-methyl-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine8-methoxy-3-methyl-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine8-methoxy-6-phenyl-3-(4-pyridyl)-11H-imidazo[1,2-c][2,3]benzodiazepine8-methoxy-6-phenyl-3-(2-pyridyl)-11H-imidazo[1,2-c][2,3]benzodiazepine8-methoxy-6-phenyl-3-(3-pyridyl)-11H-imidazo[1,2-c][2,3]benzodiazepine2,3-dimethyl-8-methoxy-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine6-(4-aminophenyl)-2,3-dimethyl-8-methoxy-11H-imidazo[1,2-c][2,3]benzodiazepine6-(4-aminophenyl)-8-methoxy-3-(2-pyridyl)-11H-imidazo[1,2-c][2,3]benzodiazepine6-(4-aminophenyl)-8-methoxy-3-(4-pyridyl)-11H-imidazo[1,2-c][2,3]benzodiazepine5-(4-aminophenyl)-8-(4-pyridyl)-11H-l,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine5-(4-aminophenyl)-9-ethyl-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepineaccording to claim
 1. 3. Pharmaceutical agent that contains a compoundof formula I according to claim
 1. 4. Process for the production of thecompound of formula I according to claim 1, in that a) a compound ofgeneral formula II

in which R¹, R², X and Y have the above meaning, is cyclized by reactionof α) z=COOC₁₋₆ alkyl with R³—N═C═O to compounds with A meaning—CO—NR³—CO— β) z=CH₂OH or —CH₂—NHR³ with phosgene to compounds with Ameaning —CH₂—O—CO— or —CH₂—NR³—CO— γ) Z=—CH₂OH with R³—CO—R⁴ tocompounds with A meaning —CH₂—O—CR³R⁴, in which R³ and R⁴ have the abovemeaning, b) a compound of formula III or IV

in which R¹, R² X and Y have the above meaning, is cyclized by reactionof α) Z′=—CH═CH—COOC₁₋₆ alkyl with borane-trimethylamine complex andboron trifluoride etherate to compounds with A meaning —(CH₂)₃— and—(CH₂)₂—CO— β) Z′=—CH═N—NH₂ in the presence of copper sulfate tocompounds with A meaning ═CH—N═N— γ) Z′—S—C₁₋₄ alkyl with hydrazinehydrate and acid anhydrides or with acid hydrazides to compounds with Ameaning ═N—N═CR³— δ) Z′=—S—C₁₋₄ alkyl with α-aminoacetals to compoundswith A meaning ═N—CR³═CR⁴— ξ) Z′═CH₂OH is converted into CH₂NH₂, thelatter is acylated and cyclized to compounds with A meaning ═CH—N═CR³—,c) a compound of formula V,

in which R¹, R² X and Y have the meaning given above, is reacted withα-aminoacetals, α-aminoketals, H₂N—CH₂—C≡C—R³ or with ammonia andα-haloketones, and then optionally nitro group R¹ and/or R² is reduced,the amino group is acylated or alkylated or converted into halogen orhydroxy or cyano or deaminated or X is dehalogenated simultaneously withthe reduction of the nitro group or in succession or hydrogen issubstituted by halogen or halogen is exchanged for another halogen,—PO₃R¹³R¹⁴, cyano, C₁₋₆ alkanoyl, C₁₋₆ alkanoyloxy, hydroxy, optionallysubstituted C₂₋₆ alkynyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, C₁₋₆ thioalkyl,COOR¹², or Y is re-etherified or the isomers are separated or the saltsare formed.
 5. Compounds of formulas IIa and IIIa, their isomers andsalts

in which R¹, R², X and Y have the above-indicated meaning and Z″ means—CH₂OH, —CHO, —COO—C₁₋₆alkyl, CH₂NHR³, or COO—C₁₋₆ alkyl and R³ has theabove-mentioned meaning.